Dysfunction of the SNARE complex in neurological and psychiatric disorders

Chen, Feng; Chen, Huiyi; Chen, Yanting; Wei, Wenyan; Sun, Yuanhong; Zhang, Lu; Cui, Lili; Wang, Yan

doi:10.1016/j.phrs.2021.105469

Cited by 25 publications

(26 citation statements)

References 218 publications

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“…To investigate the effect of Myr on the cellular modulation of neurotransmitter vesicle traffic, we evaluated the expression of genes coding for two SNARE complex proteins—T-SNARE syntaxin 1A (STX1A) and synaptosome-associated protein 25 (SNAP 25)—both of which are located at neuronal synaptic membranes, as well as V-SNARE vesicle-associated membrane protein 2 (VAMP2) and synaptophysin (SYP), which are associated with vesicle membranes [ 47 ]. As expected, fibrils significantly reduced the expression of the vesicle-associated VAMP2 proteins ( Figure 3 C) [ 47 ]. As reported in Figure 3 A–C, Myr treatment increased the expression of all of the above-mentioned genes, even under fibril treatment.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease

Mingione

Pivari

Plotegher

et al. 2021

IJMS

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Parkinson’s disease (PD) is a proteinopathy associated with the aggregation of α-synuclein and the formation of lipid–protein cellular inclusions, named Lewy bodies (LBs). LB formation results in impaired neurotransmitter release and uptake, which involve membrane traffic and require lipid synthesis and metabolism. Lipids, particularly ceramides, are accumulated in postmortem PD brains and altered in the plasma of PD patients. Autophagy is impaired in PD, reducing the ability of neurons to clear protein aggregates, thus worsening stress conditions and inducing neuronal death. The inhibition of ceramide synthesis by myriocin (Myr) in SH-SY5Y neuronal cells treated with preformed α-synuclein fibrils reduced intracellular aggregates, favoring their sequestration into lysosomes. This was associated with TFEB activation, increased expression of TFEB and LAMP2, and the cytosolic accumulation of LC3II, indicating that Myr promotes autophagy. Myr significantly reduces the fibril-related production of inflammatory mediators and lipid peroxidation and activates NRF2, which is downregulated in PD. Finally, Myr enhances the expression of genes that control neurotransmitter transport (SNARE complex, VMAT2, and DAT), whose progressive deficiency occurs in PD neurodegeneration. The present study suggests that counteracting the accumulation of inflammatory lipids could represent a possible therapeutic strategy for PD.

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Section: Resultsmentioning

confidence: 99%

Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease

Mingione

Pivari

Plotegher

et al. 2021

IJMS

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“…Recent studies on SNARE proteins have shown that their complexes are spoken in the release of neurotransmitters and that their dysfunction is the basis of neurodegenerative, neural developmental and neuropsychiatric disorders. The importance of recognizing them with increasingly precision has a significant biological impact for identifying the aforementioned pathological conditions [38]. The aim of classifying these proteins allows researchers to understand the biological pathways in which they are involved and by increasing their knowledge, they can improve the possible therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

SNARER: New Molecular Descriptors for SNARE Proteins Classification

Citarella

Biasi

Risi

et al. 2021

Preprint

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Background: SNARE proteins play an important role in different biological functions. This study aims to investigate the contribution of a new class of molecular descriptors (called SNARER) related to the chemical-physical properties of proteins in order to evaluate the performance of binary classifiers for SNARE proteins. Results: We constructed a SNARE proteins balanced dataset, D128, and an unbalanced one, DUNI, on which we tested and compared the performance of the new descriptors presented here in combination with the feature sets (GAAC, CTDT, CKSAAP and 188D) already present in the literature. The machine learning algorithms used were Random Forest, k-Nearest Neighbors and AdaBoost and oversampling and subsampling techniques were applied to the unbalanced dataset. The addition of the SNARER descriptors increases the precision for all considered ML algorithms. In particular, on the unbalanced DUNI dataset the accuracy increases in parallel with the increase in sensitivity while on the balanced dataset D128 the accuracy increases compared to the counterpart without the addition of SNARER descriptors, with a strong improvement in specificity. Our best result is the combination of our descriptors SNARER with CKSAAP feature on the dataset D128 with 92.3% of accuracy, 90.1% for sensitivity and 95% for specificity with the RF algorithm. Conclusions: The performed analysis has shown how the introduction of molecular descriptors linked to the chemical-physical and structural characteristics of the proteins can improve the classification performance. Additionally, it was pointed out that performance can change based on using a balanced or unbalanced dataset. The balanced nature of training can significantly improve forecast accuracy.

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“…Increased intracellular Ca 2+ in the pre-synaptic neuron prime the readily releasable pool of synaptic vesicles and the SNARE complex that mediates the fusion of vesicles to the membrane wall via various docking proteins ( Hackett and Ueda, 2015 ; Kaeser and Regehr, 2017 ; Chen et al, 2021 ). Carlson et al (2016) found that 6 h after cortical impact to rodents, there was a noticeable increase in SNAP-25 complex, as well as syntaxin, that steadily decreased over a 2-week period.…”

Section: Time Phase Following Impactmentioning

confidence: 99%

“… Carlson et al (2016) found that 6 h after cortical impact to rodents, there was a noticeable increase in SNAP-25 complex, as well as syntaxin, that steadily decreased over a 2-week period. This is of importance as SNAP-25 and syntaxin are two of the three main SNARE proteins responsible for vesicle-membrane fusion at the pre-synaptic terminal ( Kaeser and Regehr, 2017 ; Chen et al, 2021 ). Ahmed et al (2012) found that within 30 min following stretch damage to Drosophila motor neurons, there were elevated levels of Synaptotagmin, a Ca 2+ sensitive vesicle trafficking protein that interacts with SNAP-25, within the pre-synaptic terminal.…”

Section: Time Phase Following Impactmentioning

confidence: 99%

Hyperacute Excitotoxic Mechanisms and Synaptic Dysfunction Involved in Traumatic Brain Injury

Hoffe

Holahan

2022

Front. Mol. Neurosci.

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The biological response of brain tissue to biomechanical strain are of fundamental importance in understanding sequela of a brain injury. The time after impact can be broken into four main phases: hyperacute, acute, subacute and chronic. It is crucial to understand the hyperacute neural outcomes from the biomechanical responses that produce traumatic brain injury (TBI) as these often result in the brain becoming sensitized and vulnerable to subsequent TBIs. While the precise physical mechanisms responsible for TBI are still a matter of debate, strain-induced shearing and stretching of neural elements are considered a primary factor in pathology; however, the injury-strain thresholds as well as the earliest onset of identifiable pathologies remain unclear. Dendritic spines are sites along the dendrite where the communication between neurons occurs. These spines are dynamic in their morphology, constantly changing between stubby, thin, filopodia and mushroom depending on the environment and signaling that takes place. Dendritic spines have been shown to react to the excitotoxic conditions that take place after an impact has occurred, with a shift to the excitatory, mushroom phenotype. Glutamate released into the synaptic cleft binds to NMDA and AMPA receptors leading to increased Ca2+ entry resulting in an excitotoxic cascade. If not properly cleared, elevated levels of glutamate within the synaptic cleft will have detrimental consequences on cellular signaling and survival of the pre- and post-synaptic elements. This review will focus on the synaptic changes during the hyperacute phase that occur after a TBI. With repetitive head trauma being linked to devastating medium – and long-term maladaptive neurobehavioral outcomes, including chronic traumatic encephalopathy (CTE), understanding the hyperacute cellular mechanisms can help understand the course of the pathology and the development of effective therapeutics.

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Dysfunction of the SNARE complex in neurological and psychiatric disorders

Cited by 25 publications

References 218 publications

Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease

Inhibition of Ceramide Synthesis Reduces α-Synuclein Proteinopathy in a Cellular Model of Parkinson’s Disease

SNARER: New Molecular Descriptors for SNARE Proteins Classification

Hyperacute Excitotoxic Mechanisms and Synaptic Dysfunction Involved in Traumatic Brain Injury

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